Cholecystokinin - portrayal of an unfolding peptide messenger system

This review describes how the classic gut hormone, cholecystokinin (CCK), should be comprehended in 2025. In the early physiological tradition of studying gastrointestinal hormones, the hormones were named after the function that lead to their discovery. Hence, in 1928, the hormonal factor in the upper gut that regulated gallbladder contraction was called cholecystokinin. In 1968, Viktor Mutt and Erik Jorpes identified the porcine structure of this factor as an O-sulfated and carboxyamidated peptide of 33 amino acid residues (CCK-33). Its C-terminal bioactive heptapeptide amide turned out to be homologous to that of the antral hormone, gastrin. The structure allowed in vitro synthesis of peptide fragments for physiological studies and for production of CCK-antibodies for immunoassays and immunohistochemistry. Today, these tools have revealed CCK to be highly complex: CCK is a heterogenous, multifunctional peptide messenger system, widely expressed both in and outside the gut. Thus, the CCK gene encodes six different bioactive peptides (CCK-83, -58, -33, -22, -8, and -5) that are expressed in a cell-specific manner in O-sulfated and non-sulfated forms. Moreover, CCK peptides are not only hormones. They are also potent neurotransmitters, paracrine growth and satiety factors, anti-inflammatory cytokines, incretins, potential fertility factors and useful tumor-markers. Moreover, CCK has a phylogenetic history of nearly 600 million years. Particular interest has been given to the neuroscience of CCK, because CCK is the predominant peptide transmitter in the brain, expressed in amounts that surpass any other neuropeptide. Vice versa, the brain is the main production site of CCK in mammals.